A major goal of our research focuses on finding better and safer treatments for cancer, particularly for those for which we have no or very limited treatment options. Our natural immune system protects us from growth of cancerous cells. One of the most important innate cell types responsible for natural defense against cancer cells is the natural killer (NK) cell. When cancer cells evade NK cell-mediated destruction, the result is tumor formation. Established tumors can not only reduce NK cell numbers but also significantly inhibit their function, further hindering the immune system’s ability to eliminate the tumor. Therefore, finding a method to increase the number and function of NK cells in cancer patients could provide a safe and effective cancer treatment, particularly for cancers where limited treatment options are available, such as triple negative breast cancers and lung cancers.

"Our research focuses on finding better and safer treatments for cancer"

Critical to improving the activity of the innate immune system is having large numbers of sufficiently activated NK cells which are capable of killing cancer cells. Our laboratory is now able to generate large numbers of NK cells from a small amount of blood collected from cancer patients. Furthermore, we can stimulate these cells through unique protocols to produce highly active cancer killing NK cells. Therefore, it is possible that if these highly active NK cells from a cancer patient were injected back into the same patient (termed autologous NK cell therapy), cancers could be cleared, returning the individual to a healthy lifestyle. Recognizing the potential of NK cells as a cancer therapeutic, the immediate goal of our laboratory is to push autologous NK cell therapies into clinical trials.

The innate immune system is a critical component in combating infection. It provides a quick initial immune response to bacterial or viral challenges and shapes and stimulates the adaptive immune response that is ultimately responsible for clearing the infection. As the repertoire of cells and cytokines in the innate immune environment is vast and diverse, a few areas have become prominent research focal points within our lab.

Interleukin-15:

We are currently investigating the signalling pathway of IL-15 and its effects on the innate immune environment during viral infection. While it is well-known that IL-15 signals through lymphocytes through a trans-presentation mechanism, in which IL-15 is presented by IL-15 receptor-α to the IL-2β and common-γ-chain receptors on lymphocytes, a different mechanism of IL-15 signalling and activation may be occurring in immune cells of myeloid lineage. As a widely expressed cytokine with a crucial impact during infection, research that focuses on understanding IL-15 will have fundamental impacts on health and human disease.

Natural Killer Cells:

We are exploring the antiviral effect of natural killer cells in response to a number of viral infections, including influenza and HSV-2. We are particularly interested in the mechanisms that maintain, activate, and regulate natural killer cells in the context of viral infection.

TLR ligands:

TLR ligands have the potential to modulate and shape the induction of the innate immune response to viral infection. We are interested in understanding the protective role of TLR ligands during infection.

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HCV

Currently there is no vaccine available against hepatitis C infection. Even though recent advances have provided effective treatments for HCV, they are extremely expensive.

HCV primarily targets human liver epithelial cells, known as hepatocytes. NK cells are enriched among liver resident lymphocytes and comprise about 30% of the lymphocyte population. Their natural enrichment in the liver and their ability to eliminate virally infected hepatocytes places NK cells in a key position among effector cells in HCV infection.

Our hypothesis is that NK cells play a main role in the elimination of HCV. We know that the treatment of hepatocytes with IL-15 and IFN-γ can induce anti-HCV effects however, a significant obstacle to further understanding host-HCV interactions is the lack of relevant animal models.

Therefore, the generation of Autologous Double Humanized Mice with human liver and human immune cells provides us with a unique opportunity to study the interaction of innate and adaptive immunity with HCV infected human liver cells in a relevant in vivo model.

Humanized Mouse Model - An Experimental Model of Human Disease

Although mouse models have provided extremely valuable insights into basic physiology and pathology of human cells, tissues and organs, there are situations where they may not represent human defense/susceptibility against microbial pathogens and cancers. Studies of human cells, including human NK cells, and their interactions with human specific pathogens or cancer cells have largely been restricted to in vitro experiments and the lack of appropriate in vivo models has been a major impediment. Recent advances in the generation of humanized mice have provided a valuable means of assessing the interaction of human cells with human pathogens or cancer cells in an in vivo setting. We and others have developed this relevant pre-clinical humanized mouse model and our goal is to use this model to develop novel prevention and/or therapeutic strategies against human diseases.

"Our goal is to use this model to develop novel prevention and/or therapeutic strategies against human diseases"

Double Humanized Mouse Model for the Study of Hepatitis C Infection

Using FRG mice that have been reconstituted with human liver cells and autologous immune cells, we have generated an autologous double humanized mouse model. These mice have both a functional human immune system and human liver cells that can be infected wtih HCV to study HCV immunopathogenesis.